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Gene Review:

Brd4 - bromodomain containing 4

Mus musculus

Synonyms: Brd5, Bromodomain-containing protein 4, HUNK1, MCAP, Mcap, ...

Jang, M.K. et al., Dey, A. et al., Faraci, R.P. et al., Shang, E. et al., Nishiyama, A. et al., et al.

Houzelstein, Bullock, Lynch, Grigorieva, Wilson, Beddington,

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Disease relevance of Brd4

Specific immunity to the MCA-10 line following tumor cryosurgery was demonstrated since lymphocytes and sera from cryosurgically treated tumor-bearing mice were not cytotoxic to a different methylcholanthrene-induced sarcoma (MCAP) in C57 mice or a malignant melanoma (S91) being transferred in Balb/C mice [1].

High impact information on Brd4

Proteomic analysis revealed that Brd4 interacts with cyclinT1 and Cdk9 that constitutes core positive transcription elongation factor b (P-TEFb) [2].
In chromatin immunoprecipitation (ChIP) assays, the recruitment of P-TEFb to a promoter was dependent on Brd4 and was enhanced by an increase in chromatin acetylation [2].
Conversely, a reduction in Brd4 expression by siRNA reduced CTD phosphorylation and transcription, revealing that Brd4 is a positive regulatory component of P-TEFb [2].
Further, Brd4 colocalized with acetylated H4 and H3 in noncentromeric regions of mitotic chromosomes [3].
The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis [3].

Biological context of Brd4

Brd4 heterozygotes display pre- and postnatal growth defects associated with a reduced proliferation rate [4].
D. Kornberg (Proc. Natl. Acad. Sci. USA 95:8538-8543, 1998) and the Brd4 mutant phenotype is discussed in light of this result [4].
An increase in Brd4 expression led to increased P-TEFb-dependent phosphorylation of RNA polymerase II (RNAPII) CTD and stimulation of transcription from promoters in vivo [2].
In the present study, we investigated the role of Brd4 in cell growth regulation [5].
We found that ectopic expression of Brd4 in NIH 3T3 and HeLa cells inhibits cell cycle progression from G(1) to S [5].

Anatomical context of Brd4

Northern hybridization revealed that Brd3 is most abundant in testis, ovary, placenta, uterus, and brain; that Brd4 is rather ubiquitously expressed but is most abundant in mid-gestation embryo, testis, ovary, and brain; and that Brdt is specifically expressed in testis [6].
Subcellular localization of MAK-V/Hunk protein kinase expressed in COS-1 cells [7].

Associations of Brd4 with chemical compounds

We found that Brd4 was rapidly released from chromosomes upon treatment with antimicrotubule drugs, including the reversible agent nocodazole [8].
The reloading defect observed in Brd4+/- cells coincided with selective hypoacetylation of lysine residues on H3 and H4 [8].

Other interactions of Brd4

Indicating a preferential interaction with acetylated chromatin, Brd4 became less mobile upon increased chromatin acetylation caused by a histone deacetylase inhibitor [3].

Analytical, diagnostic and therapeutic context of Brd4

Supporting a role for MCAP in G(2)/M transition, microinjection of anti-MCAP antibody into HeLa cell nuclei completely inhibited the entry into mitosis, without abrogating the ongoing DNA replication [9].
We studied the subcellular localization of MAK-V/Hunk in COS-1 cells by immunofluorescence [7].

References

In vitro demonstration of cryosurgical augmentation of tumor immunity. Faraci, R.P., Bagley, D.H., Marrone, J., Beazley, R.M. Surgery (1975) [Pubmed]
The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Jang, M.K., Mochizuki, K., Zhou, M., Jeong, H.S., Brady, J.N., Ozato, K. Mol. Cell (2005) [Pubmed]
The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Dey, A., Chitsaz, F., Abbasi, A., Misteli, T., Ozato, K. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4. Houzelstein, D., Bullock, S.L., Lynch, D.E., Grigorieva, E.F., Wilson, V.A., Beddington, R.S. Mol. Cell. Biol. (2002) [Pubmed]
A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase. Maruyama, T., Farina, A., Dey, A., Cheong, J., Bermudez, V.P., Tamura, T., Sciortino, S., Shuman, J., Hurwitz, J., Ozato, K. Mol. Cell. Biol. (2002) [Pubmed]
Identification of unique, differentiation stage-specific patterns of expression of the bromodomain-containing genes Brd2, Brd3, Brd4, and Brdt in the mouse testis. Shang, E., Salazar, G., Crowley, T.E., Wang, X., Lopez, R.A., Wang, X., Wolgemuth, D.J. Gene Expr. Patterns (2004) [Pubmed]
Subcellular localization of MAK-V/Hunk protein kinase expressed in COS-1 cells. Korobko, E.V., Kiselev, S.L., Korobko, I.V. Cell Biol. Int. (2004) [Pubmed]
Brd4 is required for recovery from antimicrotubule drug-induced mitotic arrest: preservation of acetylated chromatin. Nishiyama, A., Dey, A., Miyazaki, J., Ozato, K. Mol. Biol. Cell (2006) [Pubmed]
A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition. Dey, A., Ellenberg, J., Farina, A., Coleman, A.E., Maruyama, T., Sciortino, S., Lippincott-Schwartz, J., Ozato, K. Mol. Cell. Biol. (2000) [Pubmed]

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